The Unexplored Importance of Fleeting Chiral Intermediates in Enzyme-catalyzed Reactions

Decades of extensive research efforts by biochemists, organic chemists and protein engineers have led to an understanding of the basic mechanisms of essentially all known types of enzymes, but in a formidable number of cases an essential aspect has been overlooked. The occurrence of short-lived chiral intermediates formed by symmetry-breaking of prochiral precursors in enzyme catalyzed reactions has been systematically neglected. These elusive species can be designated as fleeting chiral intermediates.

In a new published Perspective by Prof. Manfred T. Reetz (Max-Planck-Institut fu?r Kohlenforschung, Germany) and Dr. Marc Garcia-Borràs (IQCC) this concept has been critically analyzed and revised, opening new questions that have not been yet fully explored until today:  Do such intermediates occur in homochiral form? If so, what is the absolute configuration, and why did Nature choose that particular stereoisomeric form, even when the isolable final product may be achiral? Does the absolute configuration of a chiral product depend in any way on the absolute configuration of the fleeting chiral precursor? How does this affect the catalytic proficiency of the enzyme?

The question why Nature chose a particular chirality for a given fleeting intermediate in a naturally occurring transformation, which thus far has not been conclusively identified, needs to be addressed more closely in future work.  Does the absolute chirality of such an intermediate really matter for the proper function of that particular enzyme? The same uncertainties need to be resolved when attempting to understand the precise role of mutational results of directed enzyme evolution studies, and when aiming to (re-)design new enzyme variants. This fascinating concept of fleeting chiral intermediates will ultimately allow a full understanding of enzymatic catalysis, thereby expanding the applications of biocatalysis, and positively influencing protein engineering and drug design.

This Perspective has been accepted for publication in the Journal of the American Chemical Society:

M.T. Reetz, and M. Garcia-Borràs
“The Unexplored Importance of Fleeting Chiral Intermediates in Enzyme-Catalyzed Reactions”
J. Am. Chem. Soc. 2021, ASAP-
DOI: 10.1021/jacs.1c04551